Septic shock is a life-threatening complication of bacterial infection. Serious sepsis and septic shock are main reasons causing death in hospital infected patients. So called Sepsis means a whole-body inflammatory state (called a systemic inflammatory response syndrome, SIRS) and the presence of an obvious infection.
The main symptoms of septic shock include fever, cold dread, high respiratory rate and vague consciousness etc., which also include elevated or lowered body temperature (under 36° C. or over 38.3° C.), heart rate over 90 per minute, respiratory rate over 20 breaths per minute and white blood cell count over 12,000/cu.mm or less than 4,000/cu.mm.
The even worse situation may result in hypotension, hypoperfusion and multiple organ failure such as reduced urine flow (kidney failure), abnormal liver function and jaundice. This condition of vital organ dysfunctions due to insufficient irrigation of blood flow is called septic shock.
According to statistics, sepsis ICU death rate is about 30˜50% and represents the 11th place of main death reason in U.S. Similarly, sepsis accounts for the 13th place of main death reason of Taiwan people according to the death reason statistical bulletin of the 90th year (2001) of the Republic Era generated by Taiwan Department of Health. Because sepsis has such a high incidence and mortality rates, how to treat the disease is always a tough problem to medical profession.
Septic shock is frequently complicated by the syndrome of disseminated intravascular coagulation (DIC) due to a massive activation of the coagulation system. While body itself also provides treatment for septic shock, many biological molecules are involved in anti-coagulation pathway.
In the case of bacterial infection, the host immune cells activation occurs with the release of cytokine and non-cytokine mediators, the most notorious of which are tumor necrosis factor-alpha (TNF-a), interleukin 1(IL-1) and interleukin 6 (IL-6). These factors are implicated in the diffuse activation of a systematic inflammatory response. As a result, mediators with vasodilatory and endotoxic properties are release systematically, including prostaglandins, thromboxane A2 and nitric acid. This results in vasodilatation and endothelial damage, which lead to hypotension and capillary leak. In addition, cytokine activates the coagulation pathway, resulting in capillary microthrombi and end-organ ischemia.
There have been researches of several targets for septic shock treatment, comprising steroid, recombinant APC and many chemical compounds.
Protein C is a major anti-coagulation component which functions as vitamin K-dependent serine protease enzyme and can be cleaved by coagulation factor V and VIII into activated form. Protein S functions as a cofactor to Protein C in the inactivation of coagulation factors V and VIII. Protein C is activated in a sequence that starts with Protein C and thrombin binding to a cell surface protein thrombomodulin. The activated protein C (APC), along with protein S and a phospholipid as cofactors, degrades coagulation factor V and VIII, thus inhibit body from coagulation.
According to Bernard G R et al., 2001, recombinant human activated protein C has anti-thrombotic, anti-inflammatory and profibrinolytic properties. Based on the earlier reports, it is known that activated protein C can protect animal and human from septic shock. However, the effects of APC have remained to be discovered. Nacira S had demonstrated the protective effect of activated protein C, prevented the reduction of blood pressure induced by LPS and improved both vascular hyperactivity and myocardial performance, in rats. This effect was associated with decreased up-regulation of NF-kappaB, iNOS and MMP-9 (Nacira S et al., Crit. Care Med. 2009 January; 37(1):246-55). Although it was effective, a large randomized clinical trials demonstrated only a 6.1% absolute decrease in mortality among patients with severe sepsis, while side effect along with efficacy exists. (Bernard G. R. et al., N Engl J Med 2001, 8; 344(10):699-709).
Besides, U.S. Pat. No. 4,388,318 disclosed a method of treating endotoxin shock with a pyrimido-pyrimidine derivative. Since E. coli endotoxin may exert its hypotensive effect by activating automatic blood pressure regulatory circuit in central nervous system, the administrating of a pyrimido-pyrimidine derivative will have hypertensive effect acting on the medullary cardiovascular regulatory system.
U.S. Pat. No. 6,011,066 disclosed an amine compound of chemical formula C2H2R1R2R3NH2 for treating septic shock and a chemical structure thereof, wherein R1 and R2 are chosen from hydrogen, hydrocarbon, carboxyl group, amine group or alkyl group containing 1˜8 carbons, and R3 is chosen from hydrogen, hydrocarbon, carboxyl group, phenyl group and its substitution, acrylamine, alkylamine containing 3˜8 carbons, alkylamino-carboxylic acid or an effective amount of their salt, ester or solvate thereof. The amine compound was administrated to a subject orally or parenterally.
Among these researches, steroid has been regarded as the drug of choice to combat inflammation for a long time. But how much will be an effective dosage to treat sepsis and how long the treatment should be taken (if it did not cause side effects) have been plagued by the medical profession.
Therefore, a composition or a treating method having more effective bioactivity is demanded for reducing the mortality of sepsis and sepsis shock.